Opioid drugs like morphine, codeine, and fentanyl have conferred life-saving analgesia for million enabling medical interventions impossible without them. These benefits are off-set by dose limiting liabilities, like respiratory depression and tolerance, and by addiction. The dangers of opioids have received wide attention, as many Americans die from overdoses as from gunshot wounds and car accidents, combined. Many opioid side effects are mediated not by the canonical G protein pathway of the -opioid receptor, but by arrestin-based signaling. This has inspired a decade-long search for mu-opioid receptor agonists that activate Gi but not arrestin (?biased signaling?), leading to drugs like oliceridine. It also led to the discovery of PZM21, a novel scaffold, using structure-based discovery. PZM21 is a Gi biased mu agonist that confers analgesia without respiratory depression and without reinforcing activity. Here we have two goals: 1. Developing analogs with improved drug-like properties, and 2. Testing these analogs for analgesia, for respiratory depression, and for reinforcing liabilities. The specific aims are: Aim 1. Structure-based improvement of drug-like properties. PZM21 has remarkable signaling properties, but it has not been optimized for pharmacokinetics. Using structure-guided medicinal chemistry, we will optimize analogs for drug like properties that will move the series toward IND-enablement. Milestones: We will design and synthesize analogs that: I. improve oral bio-availability. II. Reduce clearance and increase metabolic stability. III. Increase CNS permeability. All the while we will test for and retain the potency, mu-opioid biased agonism and potentially kappa-opioid antagonism of PZM21. Aim 2. Testing PZM21 analogs in rodents for efficacy and liabilities. PZM21?s reduced respiratory depression and lack of reinforcing behavior conditioned place preference assays are encouraging. Improved PK will help us understand how these behaviors relate to signaling as a prequel to true addiction assays. Milestones: In rat studies, we will: I. Test the new analogs for analgesia in heat, cold, and mechano- sensitivity assays; the goal is to leverage the improved PK emerging from Aim 1 to achieve higher analgesia at lower doses. II. Test the new analogs for respiratory depression; seeking analogs that maintain PZM21?s lack of respiratory depression. III. Test the analogs for reinforcement in conditioned place preference assays; here too, the goal is better analgesia without reinforcement. A broad goal is to develop an SAR relating in vitro signaling to analgesia, respiratory effects, and reinforcing behavior. PZM21 is a novel chemotype with unique biology; these studies will advance the family it represents towards IND-enablement as a potential solution to the mounting opioid overdose epidemic.